tbuckley/cabot-search huggingface dataset:
Abstract 1070: Dual inhibition of AR and β-catenin induces cell death in abiraterone-resistant prostate cancer
Authors: Ibrahim M. Atawia, Prem P. Kushwaha, Shiv S. Verma, Spencer Lin, Eswar Shankar, Osama Abdel-Gawad, Sanjay Gupta
Journal: Cancer Research (2022)

Abstract Abiraterone acetate has been clinically approved for treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite exhibiting improved survival outcomes, almost all patients with advance-stage disease relapse, progressing to a more aggressive and lethal castration-resistant prostate cancer. Our pathway-related analysis and characterization of gene expression identified activation of the β-catenin pathway in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and β-catenin and their crosstalk between distinct signaling pathways causes activation of AR target genes and regulatory networks for which overcoming innate or acquired resistance remains a major challenge. Here we show that co-targeting AR and β-catenin induces cell death in abiraterone-resistant prostate cancer. For these studies, we generated abiraterone-resistant C4-2B cells (C4-2B-Abi) by growing them in progressive concentration of abiraterone 5-20µM to develop resistance and maintained in 5µM abiraterone in the culture medium for &amp;gt;20 generations. Treatment of C4-2B-Abi cells individually with abiraterone (20µM) and ICG001 (2µM) for 72 h exhibited a partial suppressive effect in cell growth compared to C4-2B parental cell line. A combination of abiraterone and ICG001 (20µM + 2µM) exhibited marked cell growth inhibition with significant increase in G1-phase cell cycle arrest, inhibition of migration and invasion in C4-2B-Abi cells, compared to the parental counterpart. Furthermore, combination treatment led to significant reduction in cell proliferation as assessed by PCNA along with reduction in the protein expression of AR, AR-v7, CDC20, PSA, β-catenin and its downstream targets, cyclinD1 and c-Myc, which were more prominent in C4-2B-Abi cells, compared to parental C4-2B cells. Co-targeting AR and β-catenin potentiated cell death in C4-2B-Abi cells as evident by increased PARP cleavage. Together, our data identify activation of the β-catenin pathway as a major mechanism contributing to abiraterone resistance and demonstrate that combined treatment with abiraterone and ICG001 appears to be an effective regimen for treatment of abiraterone-resistant cancer cells. This opens new therapeutic modality for advance-stage castration-resistant prostate cancer patients. Citation Format: Ibrahim M. Atawia, Prem P. Kushwaha, Shiv S. Verma, Spencer Lin, Eswar Shankar, Osama Abdel-Gawad, Sanjay Gupta. Dual inhibition of AR and β-catenin induces cell death in abiraterone-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1070.
Longitudinal Immune Cell Profiling in Patients With Early Systemic Lupus Erythematosus
Authors: Takanori Sasaki, Sabrina Bracero, Joshua Keegan, Lin Chen, Ye Cao, Emma Stevens, Yujie Qu, Guoxing Wang, Jennifer Nguyen, Jeffrey A. Sparks, V. Michael Holers, Stephen E. Alves, James A. Lederer, Karen H. Costenbader, Deepak A. Rao
Journal: Arthritis & Rheumatology (2022)

To investigate the immune cell profiles of patients with systemic lupus erythematosus (SLE), and to identify longitudinal changes in those profiles over time.
Abstract 1958: CTC surge
Authors: Chengsen Xue, Timothy K. Amukele
Journal: Cancer Research (2022)

Abstract Circulating Tumor Cells (CTC) are a prognostic biomarker for some types of malignant epithelial cancers and have been correlated with poor clinical outcomes. However, the routine measurement of CTC in clinical practice is still very uncommon and some key features of CTC in clinical samples are only being discovered. One of these features that we have identified by supporting CTC clinical research for over 10 years, is the presence of two distinct patient populations: one with high levels of CTC &amp;gt;220/7.5mL blood and one with levels of CTC &amp;lt;160/7.5mL. The clinical significance of this observation is still unknown, but based on this report, we propose a new oncology phenomenon: CTC Surge. Methods: In the past ten years we worked on more than half dozen clinical study projects by using CellSearch Systems by Menarini Silicon Biosystems (formerly Veridex), the only CTC technology platform approved by FDA. The Cell Search system detects CTCs by staining with surface markers coated on nanoparticle beads. The detection of CTC is linear over the reportable range of 0 to 1238 tumor cells. The FDA-approved clinical significant cut-off lines are 5 CTCs for prostate and breast cancers, and 3 for colorectal cancer. Results: All CTC results are sorted by count from low to high. There are two distinct groups roughly above 220 and below 160 per 7.5 mL of peripheral blood. The significance of a CTC enumeration &amp;gt; 220 is that there are as many as 150,000 tumor cells in circulation at the moment of sample collection. This may be the reason why some patients’ condition suddenly worsens when there is an overwhelming presence of CTCs in the bloodstream. The CTC test is a great tool for clinicians and scientists to monitor cancer diseases progression. Unlike a low number of CTCs that may actively engage in intravasation through a set of genes, the mechanism of CTC Surge likely has a completely different set of driving forces, such as internal wound, tumor necrosis and open access to blood vessels inside or surround the tumor mass. Although we do not yet know the clinical significance of our observation, the CTC test offers a simple tool to monitor the rapidly changing tumor dynamics seen in CTC Surge. Citation Format: Chengsen Xue, Timothy K. Amukele. CTC surge [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1958.
Abstract 5280: <i>TERT</i> promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma
Authors: Saeeda Omer Ahmed, Abdul K. Siraj, Sandeep K. Parvathareddy, Kaleem Iqbal, Zeeshan Qadri, Maha Al-Rasheed, Sarah Siraj, Saravanan Thangavel, Roxanne Diaz, Allianah Benito, Ingrid F. Victoria, Khawla S. AlKuraya
Journal: Cancer Research (2022)

Abstract Background: Papillary thyroid microcarcinomas (PTMCs) have been attributed to the recent increased incidence of thyroid cancer. Although indolent, a subset of PTMC could potentially develop distant metastasis (DM). This study aimed to evaluate the clinico-pathological features and molecular characteristics of PTMC and identify the risk factors for DM in PTMC patients from Middle Eastern ethnicity. Methods: We retrospectively analyzed 210 patients with histologically confirmed PTMC. Clinico-pathological associations for DM, BRAF mutation and TERT mutation were analyzed successfully in 184 patients. Multivariate analysis was performed using Cox proportional hazards model and logistic regression analysis. Results: Among the PTMC patients included in this cohort, DM was noted in 6.0%(11/184), whereas tumor relapse occurred in 29/184 (15.8%). Of the 11 cases with DM, lung metastasis occurred in 8 cases, bone metastasis in 2 cases and brain metastasis in 1 case. Presence of extrathyroidal extension and older age were significantly associated with DM. Molecular analysis showed BRAF V600E mutations to be the most frequent, being detected in 45.7% (84/184). TERT promoter mutations were detected in 16 (8.7%) cases and were significantly associated with DM and shorter metastasis-free survival in multivariate analysis. Conclusions: Our study indicates a surprisingly high frequency of TERT promoter mutation in Saudi patients with PTMC. Identifying TERT promoter mutations as an independent predictor of DM in patients with microcarcinoma could explain the inherent aggressive nature of PTMC from Middle Eastern ethnicity and magnify its role in patient risk stratification, which might help in improving therapeutic strategy for these patients. Citation Format: Saeeda Omer Ahmed, Abdul K. Siraj, Sandeep K. Parvathareddy, Kaleem Iqbal, Zeeshan Qadri, Maha Al-Rasheed, Sarah Siraj, Saravanan Thangavel, Roxanne Diaz, Allianah Benito, Ingrid F. Victoria, Khawla S. AlKuraya. TERT promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5280.
“It’s Hardly Credible” — Medical Readers and Literary Plague
Authors: Perri Klass
Journal: New England Journal of Medicine (2022)

Reading Camus' The Plague, a physician wonders why the hero doesn't prescribe sulfa drugs. If there's such a thing as "literary malpractice," she asks, is it the questionable prescribing of a fictional character or the heavy-footed perseverations of a too-literal reader?
Abstract 1132: A systems biology approach combining ProLiFiler and Cancer Data Miner for an enhanced preclinical characterization of the WEE-1 inhibitor Adavosertib
Authors: Vincent Vuaroqueaux, Daniel Feger, Anne-Lise Peille, Oliver Siedentopf, Sadhana Panzade, Sarah Ulrich, Sebastian Dempe, Heinz-Herbert Fiebig, Jan Erik Ehlert
Journal: Cancer Research (2022)

Abstract Adavosertib (AZD1775, MK-1775), a clinical stage inhibitor of the tyrosine kinase WEE1, was investigated in a cell proliferation and survival assay with 140 human cancer cell lines (CLs) representing all major tumor types (ProLiFiler platform of Reaction Biology) followed by mechanism of action (MoA) and biomarker analyses using 4HF Biotec’s Cancer Data Miner in silico platform. Adavosertib exhibited a broad anti-cancer activity across all hematological and solid tumor types with IC50 values ranging from 0.06 to 10 µM (median: 0.38 µM), matching the consistently high expression of the WEE1 gene. Among 900 reference compounds, the activity profile of adavosertib correlated best with the profiles of compounds targeting the replication stress response including other WEE1 inhibitors but also inhibitors of checkpoint kinase 1 and 2 (CHK1/2) or ataxia telangiectasia-mutated (ATM). Significant correlations were also seen with compounds blocking mitosis, DNA replication and DNA repair. Interestingly, we observed a subset of cell lines that were resistant to both DNA synthesis and PARP inhibitors but were sensitive to WEE1 inhibition. Moreover, by using multiple datasets of WEE1 inhibitors connected to the molecular annotations of CLs for a data driven biomarker screening, we identified MYC mutations as a predictive marker of sensitivity and PIK3CA or ERBB2 gene amplifications as predictors of resistance. Transcriptome analysis identified up to 900 genes for which higher expression in CLs was associated with CL sensitivity to the compound. Preliminary pathway analysis indicated that these genes are well represented among nuclear factor and Myc-regulated genes. In conclusion, our studies demonstrate broad anticancer activity of adavosertib and confirm its proposed MoA. The biomarkers we identified will facilitate the selection of pre-clinical in vivo tumor models and, if confirmed, even patient selection for clinical trials. The combined use of the ProLiFiler and Cancer Data Miner Platforms has the potential to accelerate and de-risk the development of anti-cancer agents. Citation Format: Vincent Vuaroqueaux, Daniel Feger, Anne-Lise Peille, Oliver Siedentopf, Sadhana Panzade, Sarah Ulrich, Sebastian Dempe, Heinz-Herbert Fiebig, Jan Erik Ehlert. A systems biology approach combining ProLiFiler and Cancer Data Miner for an enhanced preclinical characterization of the WEE-1 inhibitor Adavosertib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1132.
Abstract 196: Leveraging linked gut microbiome and breast cancer microfluidic chips to study the role of the estrobolome in cancer progression
Authors: Danielle S. Brasino, Sean D. Speese, Beverly M. Emerson
Journal: Cancer Research (2022)

Abstract Gut microbiota are recognized as an integral part in maintaining health, with disturbances in composition linked to disease states ranging from cancer to depression. Breast cancer patient microbiome analysis has demonstrated a correlation between dysbiosis and disease with proposed mechanisms including immune cell regulation, enhanced inflammatory signaling, and modulation of estrogen metabolism through the estrobolome. Current models lack the ability to study communication in one direction or to modulate single variables such as bacterial species or xenobiotic additions without the use of mouse models which suffer from poor translation and assessment opportunities. We have developed two microfluidic chips, one to model the gut microbiome using oxygen impermeable plastic for maintenance of anaerobic bacteria and another to culture breast cancer spheroids under constant flow. Current work has demonstrated viability and polarity maintenance in chip-cultured spheroids and initial development of polarized villus-like gut epithelium. Using these two chips, we will study the impact of breast cancer associated bacteria capable of estrogen metabolism on breast cancer tumorigenic potential. Citation Format: Danielle S. Brasino, Sean D. Speese, Beverly M. Emerson. Leveraging linked gut microbiome and breast cancer microfluidic chips to study the role of the estrobolome in cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 196.
Abstract 5056: Automated Gleason grading of digitized frozen section prostate tissue slide images
Authors: Joonyoung Cho, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang
Journal: Cancer Research (2022)

Abstract Frozen sections are used in intraoperative consultations which need rapid microscopic analysis and in certain pathological procedures that require fresh tissue. Due to the various artifacts present on frozen section tissue slides, it is difficult to automatically analyze them. We tried automatic analysis of frozen sections. Two types of segmentation deep learning models detecting Gleason patterns were used. Both models were trained from hematoxylin and eosin (H&amp;E) stained formalin-fixed, paraffin-embedded prostate tissue slide images. Each slide image was reviewed by an experienced pathologist, and all prostate cancer lesions were annotated with corresponding Gleason grades. One model was trained with H&amp;E stained images (RS model), and the other model was trained with Hematoxylin-only (H-only) stained images (H-only model). A color deconvolution method was used to generate H-only stained images from original H&amp;E stained images. In evaluation, frozen section prostate cancer slide images from The Cancer Genome Atlas (TCGA) were used. To diagnose the slide, we splitted whole slide images (WSI) into patches and analyze those patches to segment the Gleason pattern area. For the WSI result, we reconstructed the result as a whole size heatmap, then we counted the Gleason pattern to diagnose the slide as the prostate grade group. In detecting malignant cases, the RS model achieved a sensitivity of 98% and the H only model of 97%, respectively. In detecting clinically significant risk cases (grade group 2 or over), sensitivities of 99% and 96% were achieved, respectively. Most of the errors were all false-positive cases. In particular, the RS model mainly had false positives because of the ice crystal artifact, and the H-only model had many false positives for the folded part and the part suspected of being a prostatic intraepithelial neoplasia (PIN). False negatives were common in the compression artifacts for both models. We confirmed that both models showed high performance in cancer detection. In addition, they showed high accuracy in the classification of high-risk and low-risk groups of cancer. Further performance improvement can be expected with additional training of data related to artifacts or PIN. Citation Format: Joonyoung Cho, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. Automated Gleason grading of digitized frozen section prostate tissue slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5056.
Abstract 5068: Functionalized superparamagnetic nanoparticles for theranostics of membrane-bound Hsp70 positive malignant brain tumors
Authors: Ruslana Tagaeva, Vyacheslav Fedorov, Natalia Yudintceva, Luidmila Yakovleva, Boris Nikolaev, Veronica Osnach, Maxim Shevtsov
Journal: Cancer Research (2022)

Abstract Biomedical nanotechnologies based on superparamagnetic iron oxide nanoparticles (SPIONs) represent a promising instrument for malignant brain tumor theranostics. Due to their unique physico-chemical properties, they can be used for multimodal cancer therapy (including hyperthermia), diagnostics, and targeted delivery of therapeutic molecules. To enhance the tumor-homing properties of nanoparticles the latter were conjugated with bioligands (i.e., monoclonal antibodies, Fab-fragments, peptides, and proteins such serine protease granzyme B) that recognize 72 kDa membrane-bound heat shock protein (mHsp70) that is expressed on the plasma membrane of tumor cells, including multiforme glioblastoma (GBM), but not on normal corresponding cells. Therapeutic potential of magnetic conjugates can be attenuated by binding to the particles surface of granzyme B (GrB-SPIONs) that exerts pro-apoptotic activity. Functionalized particles significantly contrast-enhanced the orthotopic glioblastoma (U87 glioma in NMRI nu/nu mice, GL261 glioma in C57/Bl6 mice) in preclinical animal models when high-field (11 ) magnetic resonance tomography (Bruker) was employed. Furthermore, when GrB-SPIONs were applied, we detected a statistically significant delay of tumor progression and increase of overall animal survival. Anti-tumor activity of GrB-SPIONs was further synergistically potentiated by stereotactic radiotherapy combined with immune check-point inhibitors (i.e., CTLA-4). In conclusion, synthesized superparamagnetic nanoparticles targeting mHsp70-positive could be employed for theranostics of malignant brain tumors and translated into further clinical trials.This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement № 075-15-2020-901). Citation Format: Ruslana Tagaeva, Vyacheslav Fedorov, Natalia Yudintceva, Luidmila Yakovleva, Boris Nikolaev, Veronica Osnach, Maxim Shevtsov. Functionalized superparamagnetic nanoparticles for theranostics of membrane-bound Hsp70 positive malignant brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5068.
Abstract 599: Identification of lymphocyte activation gene 3 binding peptides using phage displayed peptide libraries for cancer immunotherapy
Authors: Seok-Min Lee, Byungheon Lee
Journal: Cancer Research (2022)

Abstract Treatment with immune checkpoint blockades against cytotoxic T lymphocyte associated protein-4, programmed cell death-1, and programmed death-ligand 1 is currently giving improved results to many cancer patients. Nevertheless, a significant proportion of cancer patients treated with immune checkpoint blockades are still largely unsatisfied with the benefits of these drugs. One of the reasons is that cancer cells also use other immune checkpoints such as lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains, and T-cell immunoglobulin and mucin-domain containing-3. LAG-3 negatively regulates activated T cells. In this study, we screened phage displayed-peptide libraries for peptides that selectively bind to LAG-3. After five rounds of screening, we selected a candidate peptide and named it LAG3Pep. LAG3Pep preferentially bound to human LAG-3-transfected HEK 293T cells over mock-transfected cells and phorbol myristate acetate/ionomycin/chloroquine-stimulated Jurkat T cells over unstimulated cells. LAG3Pep also bound to splenocytes isolated from tumor-bearing mice, suggesting the reactivity across human and mouse LAG-3. Pull-down of Jurkat T cell lysates using biotin-labeled LAG3Pep yielded a protein band of LAG-3. A competition by the pre-treatment of Jurkat T cells with a LAG-3-blocking antibody inhibited the cell binding of LAG3Pep. In addition, LAG3Pep inhibited the binding of LAG-3 protein to THP-1 cells expressing HLA-DR, a well-known LAG-3 ligand. Moreover, LAG3Pep recovered IL2 production by stimulated Jurkat T cells, which were suppressed by fibrinogen-like protein 1, another ligand of LAG-3, in the culture medium of HepG2 tumor cells. These results show that LAG3Pep selectively binds to LAG-3 and has a potential as a LAG-3 blocker for cancer immunotherapy. Citation Format: Seok-Min Lee, Byungheon Lee. Identification of lymphocyte activation gene 3 binding peptides using phage displayed peptide libraries for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 599.
Abstract 5191: BCL-2 inhibitor APG-2575 promotes anti-tumor immunity through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer
Authors: Fan Luo, Fei-teng Lu, Miao-zhen Qiu, Wen-tao Pan, Lin Zhang, Hong-yun Zhao, Li Zhang, Da-jun Yang
Journal: Cancer Research (2022)

Abstract The main challenges for immune checkpoint inhibitors (ICIs) are ascribable to tumor immunosuppressive microenvironment and a lack of sufficient activated CD8+ T cell infiltration. Modifying tumor-associated macrophages (TAMs) strategies have attracted attention for ameliorating tumor immunosuppression and improving anti-tumor immunity. Here, by applying human hematopoietic stem cell (HSC) reconstruction NSG mice and murine C57BL/6 syngeneic tumor xenografts, we demonstrated that APG-2575 combined with PD-1 blockade exerted synergistic antitumor activity, which was associated with the increased recruitment of CD8+ cytotoxic T lymphocytes. Additionally, we found that APG-2575-mediated antitumor T cell immunity is macrophage dependent, and it could function as an anticancer immune regulator that repolarizes TAMs from M2 to pro-inflammatory M1 phenotype. Mechanistically, APG-2575 enhanced M1 polarization through increasing the activated NF-κB binding to the NLRP3 promoter. In parallel, the enhanced expression of NLRP3 mediated the activation of pro-inflammatory caspases and the subsequently elevation of CCL5 and CXCL10 chemokines production by M1 macrophages. As a result, APG-2575-mediated macrophages transition could improve tumor immunosuppression, thus skewing the cytokines profiles into immunostimulatory one in the TME and further enhancing antitumor T cell immunity. These results provided a novel promising strategy for NSCLC treatment and warranted future clinical evaluation of combination therapy of APG-2575 and ICIs.Key words: BCL-2, APG-2575, ICIs, macrophages, non-small cell lung cancer. Citation Format: Fan Luo, Fei-teng Lu, Miao-zhen Qiu, Wen-tao Pan, Lin Zhang, Hong-yun Zhao, Li Zhang, Da-jun Yang. BCL-2 inhibitor APG-2575 promotes anti-tumor immunity through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5191.